Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent

Abstract

A pharmaceutical or veterinary composition, comprises a first active agent selected from a non-glucocorticoid steroid or analogues, a ubiquinone, or salts thereof, and a second active agent comprising a bronchodilator. The composition is provided in various formulations and in the form of a kit The products of this patent are applied to the prophylaxis and treatment of respiratory, lung and malignant diseases.

1 . A pharmaceutical composition, comprising a pharmaceutically or veterinarily acceptable carrier and amounts of the first and second active agents effective to treat a respiratory, lung or malignant disease, 
 (a) the first active agent being selected from a non-glucocorticoid steroid having the chemical formula                          wherein the broken line represents a single or a double bond; R is hydrogen or a halogen; the H at position 5 is present in the alpha or beta configuration or the compound of chemical formula I comprises a racemic mixture of both configurations; and R 1  is hydrogen or SO 2 OM, wherein M is selected from the group consisting of H, Na, sulfatide                          and phosphatide                          wherein R 2  and R 3 , which may be the same or different, are straight or branched (C 1 -C 14 ) alkyl or glucuronide                          or a non-glucocorticoid steroid of the chemical formula                          wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R12, R13, R14 and R19 are independently H, OR, halogen (C1-C10) alkyl or (C1-C10) alkoxy, R5 and R11 are independently OH, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20, —OPOR20R21 or (C1-C10) alky, R5 and R6 taken together are ═O, R10 and R11 taken together are ═O; R15 is (1) H, halogen, (C1-C10) alkyl, or (C1-C10) alkoxy when R16 is —C(O)OR22,(2) H, halogen, OH or (C1-C10) alkyl when R16 is halogen, OH or (C1-C10) alkyl, (3) H halogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, formyl, (C1-C10) alkanoyl or epoxy when R16 is OH, (4) OR, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20 or —OPOR20R21 when R16 is H, or R15 and R16 taken together are ═O; R17 and R18 independently (1) H, —OH, halogen, (C1-C10) alkyl or —(C1-C10) alkoxy when R6 is H OR, halogen. (C1-C10) alkyl or —C(O)OR22, (2) H, (C1-C10 alkyl).amino, ((C1-C10) alkyl)n amino-(C1-C10) alkyl, (C1-C10) alkoxy, hydroxy —(C1-C10) alkyl, (C1-C10) alkoxy —(C1-C10) alkyl, (halogen)m (C1-C10) alkyl, (C1-C10) alkanoyl, formyl, (C1-C10) carbalkoxy or (C1-C10) alkanoyloxy when R15 and R16 taken together are ═O, (3) R17 and R18 taken together are ═O; (4) R17 or R18 taken together with the carbon to which they are attached form a 3-6 member ring containing 0 or 1 oxygen atom; or (5) R15 and R17 taken together with the carbons to which they are attached form an epoxide ring; R20 and R21 are independently OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether; R22 is H, (halogen)m (C1-C10) alkyl or (C1-C10) alkyl; n is 0, 1 or 2; and m is 1, 2 or 3; or pharmaceutically or veterinarily acceptable salts thereof; and/or    a ubiquinone or pharmaceutically or veterinarily acceptable salt thereof, wherein the ubiquinone has the chemical formula                          wherein n is 1 to 12; and    (b) the second active agent comprising a bronchodilating agent.    
     
     
         2 . The composition of  claim 1 , wherein the first active agent has the formula COQ n , wherein n is 1 to 10.  
     
     
         3 . The composition of  claim 1 , wherein the first active agent has the formula CoQ n , wherein n is 6 to 10.  
     
     
         4 . The composition of  claim 1 , wherein the first active agent has the formula CoQ n , wherein n is 10.  
     
     
         5 . The composition of  claim 1 , comprising about 0.01 to about 99.9% w/w first and second active agent.  
     
     
         6 . The composition of  claim 5 , comprising about 1 to about 20% w/w first and second active agents.  
     
     
         7 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (1), wherein R and R 1  are each hydrogen and the broken line represents a double bond, or dehydroepiandrosterone.  
     
     
         8 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is Br, R 1  is H, and the broken line represents a double bond, or 16-alpha bromoepiandrosterone.  
     
     
         9 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is F, R 1  comprises H and broken line represents a double bond, or 16-alpha-fluoro epiandrosterone.  
     
     
         10 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R and R 1  are each hydrogen and the broken line represents a double bond, or etiocholanolone.  
     
     
         11 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is H, R 1  is SO 2 OM and M is a sulfatide group as defined above, and the broken line represents a single bond, or dehydroepiandrosterone sulfate.  
     
     
         12 . The composition of  claim 1 , wherein in the compound of formula (I), R is halogen selected from Br, Cl or F, R 1  is H, and the broken line represents a double bond.  
     
     
         13 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), which is 16-alpha-fluoro epiandrosterone or 16-alpha-bromo epiandrosterone.  
     
     
         14 . The composition of  claim 1 , wherein first active agent comprises the compound of formula (III), wherein R 15  and R 16   1 together from =0.  
     
     
         15 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (m) or (IV), wherein R 5  is OH.  
     
     
         16 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (III) or (IV), wherein R 5  is OSO 2 R 20 .  
     
     
         17 . The composition of  claim 1 , wherein the first active agent comprises a non-glucocorticoid steroid of formula (III) or (TV), wherein R 20  is H.  
     
     
         18 . The composition of  claim 1 , wherein the second active agent is selected from β2 adrenergic agonists, anti-cholinergic agents, anti-histaminic agents, adenosine receptor antagonists or glucocorticosteroids.  
     
     
         19 . The composition of  claim 18 , wherein the second active agent comprises a β2 adrenergic agonist selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide.  
     
     
         20 . The composition of  claim 18 , wherein the second active agent comprises a glucocorticosteroid.  
     
     
         21 . The composition of  claim 18 , wherein second active agent comprises an anti-cholinergic agent.  
     
     
         22 . The composition of  claim 18 , wherein the second active agent comprises a theophylline.  
     
     
         23 . The composition of  claim 1 , further comprising an agent selected from other therapeutic or bioactive agents, preservatives, anti-oxidants, flavoring agents, volatile oils, buffering agents, dispersants or surfactants.  
     
     
         24 . The composition of  claim 23 , wherein the other therapeutic or bioactive agents are selected from analgesics, pre-menstrual medications, menopausal agents, anti-aging agents, anti-anxyolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schyzophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti-angyogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents, hair growth agents, analgesics, pre-menstrual medications, anti-menopausal agents, hormones, anti-aging agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Crohn's disease, ulcerative colitis, autoimmune disease, lupus erythematosus, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound and burn healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, agents for reperfusion injury, counteracting appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents or hair growth agents.  
     
     
         25 . The composition of  claim 1 , which is a systemic or topical formulation, and wherein the carrier comprises a gaseous, solid or liquid carrier.  
     
     
         26 . The formulation of  claim 25 , selected from an oral, nasal, inhalable, topical, parenteral or transdermal formulation.  
     
     
         27 . The formulation of  claim 26 , selected from oral, intrabuccal, intrapulmonary, respirable, inhalable, nasal, rectal, intrauterine, vaginal, intratumor, intracranial, subcutaneous, intravascular, sublingual, intravenous, intrathecal, transdermal, intradermal, intracavitary, implantable, iontophoretic, intraocular, ophthalmic, intraarticular, otical, intravenous, intramuscular, intraglandular, intraorgan, intralymphatic, slow release or enteric coating formulations.  
     
     
         28 . The formulation of  claim 26 , which is an oral formulation.  
     
     
         29 . The oral formulation of  claim 28 , which is selected from capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions or emulsions.  
     
     
         30 . The oral formulation of  claim 28 , further comprising an enteric coating.  
     
     
         31 . The formulation of  claim 26 , which is a solution, suspension or emulsion selected from aqueous or non-aqueous liquid solutions or suspensions, or oil-in-water or water-in-oil emulsions.  
     
     
         32 . The formulation of  claim 26 , which is a buccal or sub-lingual formulation.  
     
     
         33 . The formulation of  claim 26 , which is a parenteral formulation.  
     
     
         34 . The parenteral formulation of  claim 33 , in injectable form.  
     
     
         35 . The formulation of  claim 26 , which is a topical formulation.  
     
     
         36 . The formulation of  claim 35 , which is selected from ointments, creams, lotions, pastes, gels, sprays, aerosols or oils; and may further comprise a carrier selected from vaseline, lanoline, polyethylene glycols, alcohols or trans-dermal enhancers.  
     
     
         37 . The formulation of  claim 26 , which is a transdermal formulation.  
     
     
         38 . The transdermal formulation of  claim 37 , which is in the form of a patch.  
     
     
         39 . The transdermal formulation of  claim 37 , which is an iontophoretic formulation.  
     
     
         40 . The iontophoretic formulation of  claim 39 , which is selected from iontophoretic solutions, suspensions or emulsions, and which may further comprise a buffer.  
     
     
         41 . The formulation of  claim 26 , which is a nasal, inhalable, respirable, intrapulmory or intratracheal formulation.  
     
     
         42 . The nasal, inhalable, respirable, intrapulmonary or intratracheal formulation of  claim 41 , which is an aerosol or spray comprising liquid or solid powdered particles.  
     
     
         43 . The inhalable or respirable formulation of  claim 41 , comprising particles of about 0.05 to about 10 μm in size.  
     
     
         44 . The inhalable or respirable formulation of  claim 43 , comprising particles about 1 to about 5 μm in size.  
     
     
         45 . The nasal, intrapulmonary or intratracheal formulation of  claim 41 , comprising particles about 10 to about 100 μm in size.  
     
     
         46 . The nasal, intrapulmonary or intratracheal formulation of  claim 45 , comprising particles about 20 to about 50 μm in size.  
     
     
         47 . The composition of  claim 1 , in bulk or in single- or multi-dose form.  
     
     
         48 . The single- or multi-dose form of the composition of  claim 47 , which is provided in sealed ampoules, vials, cartridges or blisters.  
     
     
         49 . The composition of  claim 1 , which is freeze-dried or lyophilized.  
     
     
         50 . A kit, comprising a delivery device, and the formulation of  claim 41 .  
     
     
         51 . The kit of  claim 48 , wherein the delivery device comprises an aerosol or spray generator.  
     
     
         52 . The kit of  claim 51 , wherein the aerosol generator comprises an inhaler.  
     
     
         53 . The kit of  claim 51 , wherein the inhaler delivers individual pre-metered doses of the formulation  
     
     
         54 . The kit of  claim 52 , wherein the inhaler comprises a nebulizer or insufflator.  
     
     
         55 . The kit of  claim 50 , wherein the delivery device comprises a compression inhaler, and the formulation comprises a suspension or solution in an aqueous, or non-aqueous liquid, or an oil-in-water, or water-in-oil emulsion.  
     
     
         56 . The kit of  claim 50 , wherein the formulation is provided in a capsule, cartridge or blister, which may be a pierceable or openable capsule, cartridge or blister.  
     
     
         57 . The kit of  claim 50 , wherein the delivery device is pressurized and it operates with the aid of a propellant.  
     
     
         58 . A method for treatment of a respiratory, lung or malignant disorder or condition, or for reducing levels of, or sensitivity to, adenosine or adenosine receptors, or for increasing surfactant or ubiquinone levels in a subject in need of treatment, comprising simultaneously, sequentially or separately administering to a subject in need of treatment prophylactically or therapeutically effective amounts of the first and second active agents of  claim 1 .  
     
     
         59 . The method of  claim 58 , wherein the disorder or condition comprises asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), dispnea, emphysema, wheezing, pulmonary hypertension, pulmonary fibrosis, hyper-responsive airways, increased adenosine or adenosine receptor levels, adenosine hyper-sensitivity, infectious diseases, pulmonary bronchoconstriction, respiratory tract inflammation or allergies, lung surfactant or ubiquinone depletion, chronic bronchitis, bronchoconstriction, difficult breathing, impeded or obstructed lung airways, adenosine test for cardiac function, pulmonary vasoconstriction, impeded respiration, Acute Respiratory Distress Syndrome (ARDS), administration of adenosine or adenosine level increasing drugs, infantile Respiratory Distress Syndrome (infantile RDS), pain, allergic rhinitis, cancer, or chronic bronchitis.  
     
     
         60 . The method of  claim 58 , wherein the first active agent comprises a non-glucocorticoid steroid formula (I), (III) or (IV), or salt thereof, and is administered in an amount of about 0.05 to about 2000 mg/kg body weight/day.  
     
     
         61 . The method of  claim 60 , wherein the non-glucocorticoid steroid of formula (I), (III) or (IV), or salt thereof, is administered in an amount of about 1 to about 500 mg/kg/day.  
     
     
         62 . The method of  claim 61 , wherein the non-glucocorticoid steroid of formula (I), (III) or (IV), or salt thereof, is administered in an amount of about 2 to about 100 mg/kg/day.  
     
     
         63 . The method of  claim 58 , wherein the first active agent is a ubiquinone of formula (II) or salt thereof, and it is administered in an amount of about 1 to 150 mg/kg body weight/day.  
     
     
         64 . The method of  claim 63 , wherein the ubiquinone of formula (II) or salt thereof is administered in an amount of about 30 to about 100 mg/kg/day.  
     
     
         65 . The method of  claim 64 , wherein the ubiquinone of formula (II) or salt thereof is administered in an amount of about 5 to about 50 mg/kg/day.  
     
     
         66 . The method of  claim 58 , wherein the respiratory or lung disease or condition is associated with an infectious disease, respiratory tract allergies or surfactant depletion.  
     
     
         67 . The method of  claim 58 , wherein the disorder or condition comprises COPD.  
     
     
         68 . The method of  claim 58 , wherein the disorder or condition comprises asthma.  
     
     
         69 . The method of  claim 58 , wherein the disorder or condition comprises RDS.  
     
     
         70 . The method of  claim 58 , wherein the disorder or condition comprises allergic rhinitis.  
     
     
         71 . The method of  claim 58 , wherein the disorder or condition comprises pulmonary fibrosis.  
     
     
         72 . The method of  claim 58 , wherein the disorder or condition comprises bronchoconstriction, wheezing, difficulty breathing or hypoxia.  
     
     
         73 . The method of  claim 58 , wherein the respiratory or lung disease or condition comprises cystic fibrosis.  
     
     
         74 . The method of  claim 58 , wherein the respiratory or lung disease or condition comprises emphysema.  
     
     
         75 . The method of  claim 58 , wherein the respiratory or lung disease or condition comprises dyspnea.  
     
     
         76 . The method of  claim 58 , wherein the first active agent comprises DHEA or DHEA-S and ubiquinone, and the second active agent comprises a β2 adrenergic agonist selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide.  
     
     
         77 . The method of  claim 58 , wherein the subject is a human or a non-human animal.  
     
     
         78 . The method of  claim 58 , which is a prophylactic method.  
     
     
         79 . The method of  claim 58 , which is a therapeutic method.  
     
     
         80 . The method of  claim 58 , wherein the respiratory disease comprises bronchoconstriction, lung inflammation or allergies, decreased lung surfactant or decreased ubiquinone, or DHEA or DHEA-S levels.  
     
     
         81 . The method of  claim 58 , wherein the first active agent comprises a ubiquinone; and the second active agent comprises a β2 adrenergic agonist agent selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide.  
     
     
         82 . The method of  claim 58 , wherein the first active agent comprises DHEA; and is administered in an amount of about 2 to about 200/mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 pg per day wherein the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day.  
     
     
         83 . The method of  claim 58 , wherein the first active agent comprises DHEA Sulfate (DHEA-S) and is administered in an amount of about 1 to about 150 /mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day.  
     
     
         84 . The method of  claim 58 , wherein the first agent comprises a ubiquinone of formula (II), or salt thereof, and it is administered in an amount about 0.1 to about 1200 mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day.  
     
     
         85 . The method of  claim 58 , wherein the first and second active agents are administered by inhalation, into the airways or respiration, intrapulmonarily, nasally, orally, bucally, rectally, vaginally, into a tumor or fibroma, parenterally, sublingually, transdermally, topically, iontophorically, intracavitarily, by implant, sub-lingually, opthalmically, otically, intraarticularly, intralymphatically, by slow or sustained release or interically coated.  
     
     
         86 . The method of  claim 85 , wherein the agents are administered nasally, intrapulmonarily, by inhalation or into the respiratory airways.  
     
     
         87 . The method of  claim 86 , wherein the agents are administered as a liquid or powdered aerosol or spray of particle size about 0.05 to about 10 μm.  
     
     
         88 . The method of  claim 87 , wherein the agents are administered as a liquid or powdered aerosol or spray of particle size about 10 to about 50 μm.